Production method for alpha-fluoro acrylic acid esters

ABSTRACT

An object of the present invention is to provide a process for producing α-fluoroacrylic acid esters at a high starting material conversion and a high yield. 
     The present invention provides, as a means to achieve the object, a process for producing a compound represented by formula (1): 
     
       
         
         
             
             
         
       
         
         wherein R 2  and R 2  are the same or different and each represent alkyl, fluoroalkyl, aryl optionally substituted with at least one substituent, halogen, or hydrogen; and 
         R 3  represents alkyl, fluoroalkyl, or aryl optionally substituted with at least one substituent,
       the process comprising step A of   reacting a compound represented by formula (2):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein the symbols are as defined above, with carbon monoxide and an alcohol represented by formula (3): 
           
         
       
    
       R 3 —OH   ( 3 )
         wherein the symbol is as defined above, in the presence of a transition metal complex catalyst containing at least one bidentate phosphine ligand and a base to thereby obtain the compound represented by formula (1).

TECHNICAL FIELD

The present invention relates to a process for producing α-fluoroacrylicacid esters.

BACKGROUND ART

α-Fluoroacrylic acid esters are useful, for example, as a syntheticintermediate for medical drugs (e.g., antibiotic drugs), a syntheticintermediate for cladding materials of optical fibers, a syntheticintermediate for painting materials, a synthetic intermediate forsemiconductor resist materials, and a monomer for functional polymers.

Examples of conventional processes for producing an α-fluoroacrylic acidester in an excellent yield include the process proposed in PatentDocument 1 for producing an α-fluoroacrylic acid ester by subjecting anα-fluorophosphono acetate and paraformaldehyde to a condensationreaction, the process being characterized in that the condensationreaction is carried out in an aqueous medium in the presence of a weakinorganic base (Patent Literature 1).

CITATION LIST Patent Literature

-   Patent Literature 1: JPH05-201921A

SUMMARY OF INVENTION Technical Problem

The yield of α-fluoroacrylic acid ester according to the processdisclosed in Patent Document 1, however, is 82% at most, and a processfor achieving a higher yield is desired.

In particular, it is desirable that synthetic intermediates, forexample, for producing medical drugs, contain by-products in anextremely low amount from the standpoint of medical drug safety; thus, ahigh selectivity of α-fluoroacrylic acid ester is required. Nonetheless,in the conventional processes for producing a 2-fluoroacrylic acidcompound, the reaction is typically complicated because of thegeneration of derivatives or so on; the yield of the 2-fluoroacrylicacid compound is low; and the separation of the 2-fluoroacrylic acidcompound is difficult. Therefore, conventional processes have adisadvantage in industrial application in that by-products must beremoved to increase the purity of the 2-fluoroacrylic acid compound,whereby large amounts of waste fluids and waste materials are produced.

The present inventors thus developed the following process for producingα-fluoroacrylic acid esters at a high starting material conversion, ahigh selectivity, and a high yield, and filed a patent application(PCT/JP2013/073446, unpublished) for the process for producing acompound represented by formula (1′):

wherein R represents alkyl optionally substituted with at least onefluorine atom,

the process comprising step A of

reacting a compound represented by formula (2′):

wherein X represents a bromine atom or a chlorine atom, with carbonmonoxide and an alcohol represented by formula (3′):

R—OH   (3′)

wherein the symbol is as defined above, in the presence of a transitionmetal catalyst and a base to thereby obtain the compound represented byformula (1′).

However, the inventors further aimed to provide a process for producinga-fluoroacrylic acid esters at a high starting material conversion and ahigh yield using a small amount of a catalyst.

Solution to Problem

The present inventors found that a compound represented by formula (1),which is an α-fluoroacrylic acid ester, is produced by the followingprocess at a high starting material conversion and a high yield, andcompleted the present invention.

A process for producing a compound represented by formula (1)

wherein R¹ and R² are the same or different and each represent alkyl,fluoroalkyl, aryl optionally substituted with at least one substituent,halogen, or hydrogen; and

-   R³ represents alkyl, fluoroalkyl, or aryl optionally substituted    with at least one substituent,    -   the process comprising step A of    -   reacting a compound represented by formula (2):

wherein the symbols are as defined above, with carbon monoxide and analcohol represented by formula (3):

R³—OH   (3)

wherein the symbol is as defined above, in the presence of a transitionmetal complex catalyst containing at least one bidentate phosphineligand and a base.

Specifically, the present invention encompasses the following subjectmatter.

Item 1.

A process for producing a compound represented by formula (1):

wherein R¹ and R² are the same or different and each represent alkyl,fluoroalkyl, aryl optionally substituted with at least one substituent,halogen, or hydrogen; and

-   R³ represents alkyl, fluoroalkyl, or aryl optionally substituted    with at least one substituent,    -   the process comprising step A of    -   reacting a compound represented by formula (2):

wherein the symbols are as defined above, with carbon monoxide and analcohol represented by formula (3):

R³—OH   (3)

wherein the symbol is as defined above, in the presence of a transitionmetal complex catalyst containing at least one bidentate phosphineligand and a base to thereby obtain the compound represented by formula(1).

Item 2.

The process according to Item 1, wherein R¹ represents hydrogen or aryl,and R² represents hydrogen or aryl.

Item 3.

The process according to Item 1 or 2, wherein the transition metal ispalladium.

Item 4.

The process according to any one of Items 1 to 3, wherein the at leastone bidentate phosphine ligand contains two aromatic rings that arelinked through an oxygen-containing linking group.

Item 5.

The process according to any one of Items 1 to 4, wherein the transitionmetal complex catalyst is used in an amount of 0.001 moles or less permole of the compound represented by formula (2).

Item 6.

The process according to any one of Items 1 to 5, wherein the base is anamine.

Item 7.

The process according to any one of Items 1 to 6, wherein step A isperformed at a temperature within the range of 60 to 120° C.

Advantageous Effects of Invention

The process according to the present invention enables the production ofα-fluoroacrylic acid esters at a high starting material conversion and ahigh yield.

DESCRIPTION OF EMBODIMENTS

As used herein, examples of “alkyl” include C₁₋₆ alkyl, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, neopentyl, and hexyl.

As used herein, “fluoroalkyl” refers to alkyl having at least onehydrogen atom replaced with a fluorine atom. “Fluoroalkyl” encompassesperfluoroalkyl. “Perfluoroalkyl” refers to alkyl having all hydrogenatoms replaced with fluorine atoms.

As used herein, “alkoxy” refers to alkyl-O— group.

As used herein, examples of “acyl” include alkanoyl (i.e.,alkyl-CO-group).

As used herein, examples of “ester group” include alkyl carbonyl oxy(i.e., alkyl-CO-O-group), and alkoxy carbonyl (i.e., alkyl-O—CO-group).

As used herein, examples of “cycloalkyl” include C₃₋₈ cycloalkyl, suchas cyclopentyl, cyclohexyl, and cycloheptyl.

As used herein, examples of “aryl” include C₆₋₁₀ aryl, such as phenyland naphthyl.

The process of the present invention for producing a compoundrepresented by formula (1):

wherein R¹ and R² are the same or different and each represent alkyloptionally substituted with at least one substituent, aryl optionallysubstituted with at least one substituent, halogen, or hydrogen; and

-   R³ represents alkyl, fluoroalkyl, or aryl optionally substituted    with at least one substituent

comprises:

step A of reacting a compound represented by formula (2):

wherein the symbols are as defined above, with carbon monoxide and analcohol represented by formula (3):

R³—OH   (3)

wherein the symbol is as defined above, in the presence of a transitionmetal complex catalyst containing at least one bidentate phosphineligand and a base to thereby obtain the compound represented by formula(1).

Preferable examples of the substituent in “aryl optionally substitutedwith at least one substituent” represented by R¹ include fluorine,alkoxy, acyl, ester group, cyano, nitro, alkyl, and fluoroalkyl, andmore preferable examples include fluorine.

R¹ is preferably hydrogen or aryl, and is particularly preferablyhydrogen.

Preferable examples of the substituent in “aryl optionally substitutedwith at least one substituent” represented by R² include fluorine,alkoxy, acyl, ester group, cyano, nitro, alkyl, and fluoroalkyl, andmore preferable examples include fluorine.

R² is preferably hydrogen or aryl, and is particularly preferablyhydrogen.

R³ is preferably methyl, ethyl, or fluoroalkyl, and is particularlypreferably methyl.

In a preferable embodiment of the present invention, R¹ is hydrogen oraryl, and R² is hydrogen or aryl.

The compound represented by formula (1) is preferably 2-fluoroacrylicacid methyl ester or 2-fluoroacrylic acid ethyl ester, and isparticularly preferably 2-fluoroacrylic acid methyl ester.

The compound represented by formula (2) is a known compound that can beproduced by a known process, or is commercially available.

The alcohol represented by formula (3) is preferably methanol, ethanol,trifluoroethanol, pentafluoropropanol, or hexafluoroisopropanol, and isparticularly preferably methanol.

The alcohol represented by formula (3) can also serve as a solvent forthe reaction in step A.

The alcohol represented by formula (3) used as a reaction startingmaterial for step A is used in an amount of typically 1 to 500 moles,and preferably about 1.1 to 50 moles per mole of the compoundrepresented by formula (2).

When the alcohol represented by formula (3) is also used as a solventfor the reaction in step A, the alcohol is used in large excess relativeto the amount of the compound represented by formula (2). Specifically,when a solvent other than the alcohol is not used, the alcohol may beused in an amount of typically 0.1 to 20 L, preferably about 0.2 to 5 L,or 0.5 to 10 L, or about 1 to 5 L per mole of the compound representedby formula (2).

The reaction pressure in step A is not particularly limited, and may be,for example, atmospheric pressure, or a pressure higher than atmosphericpressure. Step A is preferably carried out in a container such as anautoclave, and the carbon monoxide used as a reactant of step A can beintroduced into the container by using a carbon monoxide-containing gas,such as purified carbon monoxide gas. The pressure of carbon monoxide istypically 0 to 10 MPaG, and preferably 0.25 to 4 MPaG.

The “transition metal complex catalyst containing at least one bidentatephosphine ligand” used in step A contains, for example, at least onetransition metal selected from the group consisting of nickel,palladium, platinum, rhodium, ruthenium, iridium, and cobalt.

Specifically, examples of transition metal complex catalysts usable instep A include nickel complex catalysts, palladium complex catalysts,platinum complex catalysts, rhodium complex catalysts, ruthenium complexcatalysts, iridium complex catalysts, and cobalt complex catalysts. Thepalladium complex catalysts are preferably zero-valent palladium complexcatalysts, or divalent palladium complex catalysts.

The transition metal is preferably selected from the group consisting ofnickel, cobalt, and palladium, and is particularly preferably palladium.

The “bidentate phosphine ligand” in the “transition metal complexcatalyst containing at least one bidentate phosphine ligand” used instep A can be, for example, a bidentate phosphine ligand in which atleast one substituent selected from the group consisting of alkyl,cycloalkyl, and aryl is attached to each phosphorus atom.

The bidentate phosphine ligand in the “transition metal complex catalystcontaining at least one bidentate phosphine ligand” used in step Apreferably contains two aromatic rings that are linked through anoxygen-containing linking group.

Examples of the “oxygen-containing linking group” include divalentgroups, such as —O— and —(CH₂)_(n1)—O—(CH₂)_(n2)— wherein n1 and n2 arethe same or different and each represent an integer of 0 to 6.

Examples of the aromatic ring include benzene ring.

The two aromatic rings may be further linked through another linkinggroup in addition to the “oxygen-containing linking group.”

The two aromatic rings each preferably have one phosphorus atom attachedto one of the atoms constituting the ring.

Specific examples of “bidentate ligand” in the “transition metal complexcatalyst containing at least one bidentate phosphine ligand” usable instep A include 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane,1,5-bis(diphenylphosphino)pentane, bis(diphenylphosphinophenyl)ether,bis(dicyclohexylphosphinophenyl)ether,4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene,1,1′-bis(diphenylphosphino)ferrocene,1,1′-bis(di-tert-butylphosphino)ferrocene,1,1′-bis(dicyclohexylphosphino)ferrocene,1,1′-bis(diisopropylphosphino)ferrocene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,4,6-bis(diphenylphosphino)phenoxazine,1,3-bis(diisopropylphosphino)propane,1,4-bis(diisopropylphosphino)butane,1,3-bis(dicyclohexylphosphino)propane, and1,4-bis(dicyclohexylphosphino)butane.

The “transition metal complex catalyst containing at least one bidentatephosphine ligand” used in step A may contain at least one ligand otherthan the “bidentate phosphine ligand,” and examples of such ligandsinclude chlorine ligands.

Specific examples of the “transition metal complex catalyst containingat least one bidentate phosphine ligand” usable in step A includedichloro[1,2-bis(diphenylphosphino)ethane]palladium(II),dichloro[1,3-bis(diphenylphosphino)propane]palladium(II),dichloro[1,4-bis(diphenylphosphino)butane]palladium(II),dichloro[1,5-bis(diphenylphosphino)pentane]palladium(II),dichloro[bis(diphenylphosphinophenyl)ether]palladium(II),dichloro[bis(dicyclohexylphosphinophenyl)ether]palladium(II),dichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II),dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II),dichloro[1,1′-bis(diisopropylphosphino)ferrocene]palladium(II),dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II),dichloro[4,6-bis(diphenylphosphino)phenoxazine]palladium(II),dichloro[1,3-bis(diisopropylphosphino)propane]palladium(II),dichloro[1,4-bis(diisopropylphosphino)butane]palladium(II),dichloro[1,3-bis(dicyclohexylphosphino)propane]palladium(II), anddichloro[1,4-bis(dicyclohexylphosphino)butane]palladium(II).

The number of bidentate phosphine ligands coordinated to the transitionmetal varies depending on the oxidation number of the transition metalor other factors, but is preferably, for example, one or two.

The transition metal complex catalyst may be a reagent added to thereaction system, or a catalyst that is generated in the reaction system.

Preferable examples of precursors of transition metal complex catalystsgenerated in the reaction system include palladium chloride, palladiumbromide, palladium acetate, bis(acetylacetonato)palladium(II), Pd₂(dba)₃(dba represents dibenzylideneacetone), Pd(COD)₂ (COD representscycloocta-1,5-diene), and Pd(PPh₃)₄ (Ph represents phenyl).

The “transition metal complex catalyst containing at least one bidentatephosphine ligand” used in step A may be a heterogeneous catalystobtained by having the catalyst dispersed in or supported on a polymer,such as polystyrene and polyethylene.

Such a heterogeneous catalyst has advantages, for example, catalystrecovery, in the process. Examples of the specific structure of thecatalyst include a structure in which a transition metal atom isimmobilized by a polymer phosphine formed by introducing phosphines intoa crosslinked polystyrene (PS) chain, as shown in the following chemicalformula:

wherein PS represents polystyrene and Ph represents phenyl.

The “bidentate phosphine ligand” in this example is composed oftriarylphosphines formed by binding one phenyl group oftriphenylphosphine to a polymer chain as shown by the following chemicalformula

wherein PS represents polystyrene, and Ph represents phenyl.

The “transition metal complex catalyst containing at least one bidentatephosphine ligand” used in step A may be a supported catalyst in whichthe transition metal is supported on a carrier. Such a supportedcatalyst has a cost advantage because the catalyst is recyclable.

Examples of carriers include carbon, alumina, silica-alumina, silica,barium carbonate, barium sulfate, calcium carbonate, titanium oxide,zirconium oxide, and zeolite.

The upper limit of the amount of the transition metal catalyst is, forexample, 0.05 moles, 0.01 moles, 0.005 moles, 0.002 moles, 0.001 moles,0.0005 moles, 0.0001 moles, or 0.00006 moles per mole of the compoundrepresented by formula (2).

The lower limit of the amount of the transition metal catalyst istypically 0.000001 moles, 0.00001 moles, and more preferably 0.00002moles, or 0.00004 moles per mole of the compound represented by formula(2).

Step A is performed in the presence of a base.

Examples of bases usable in step A include amines, inorganic bases, andorganic metal bases.

Examples of amines include triethylamine, tri(n-propyl)amine,tri(n-butyl)amine, diisopropylethylamine, cyclohexyldimethylamine,pyridine, lutidine, γ-collidine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene, 1,5-diazabicyclo[4,3,0]-5-nonene,and 1,4-diazabicyclo[2,2,2]octane.

Examples of inorganic bases include lithium hydroxide, potassiumhydroxide, sodium hydroxide, calcium hydroxide, lithium carbonate,sodium carbonate, potassium carbonate, sodium hydrogen carbonate, andpotassium hydrogen carbonate.

Examples of organic metal bases include organic alkali metal compounds,such as butyllithium, t-butyllithium, phenyllithium, sodiumtriphenylmethyl, and sodium ethyl; organic alkali earth metal compounds,such as methylmagnesium bromide, dimethylmagnesium, phenylmagnesiumchloride, phenylcalcium bromide, and bis(dicyclopentadiene)calcium; andalkoxides, such as sodium methoxide, and t-butyl methoxide.

Preferable examples of bases include lithium hydroxide, triethylamine,potassium carbonate, and lithium carbonate. More preferable examples ofbases include triethylamine, potassium carbonate, and lithium carbonate.Particularly preferable examples of bases include triethylamine.

The bases can be used singly, or in a combination of two or more.

The amount of the base is typically 0.2 to 5 moles, and preferably about0.5 to 3 moles per mole of the compound represented by formula (2).

Step A is performed at a temperature within the range of typically 10 to150° C., preferably 50 to 120° C., more preferably 60 to 110° C., andstill more preferably 70 to 110° C.

Performing step A at an excessively low temperature is likely to lowerthe starting material conversion and the yield.

When step A is performed at an excessively high temperature, thereaction mixture obtained after the reaction in step A may contain astarting material (i.e., the compound represented by formula (1)),by-products, or decomposition products, which may be observed inanalysis conducted by the analysis described below.

Analysis Method

After completion of the reaction, hexafluorobenzene is added as aninternal standard substance, and the resulting mixture is stirred. Themixture is then allowed to stand for a short period of time toprecipitate the salt. The supernatant is diluted with deuteratedchloroform, and subjected to quantification based on ¹⁹F-NMR integralvalues.

In step A, in addition to the alcohol represented by formula (3), whichcan also serve as a solvent, other solvent(s) may be used. When othersolvent(s) are used, the amount of the alcohol represented by formula(3) can be reduced.

Examples of such solvents include non-aromatic hydrocarbon solvents,such as pentane, hexane, heptane, octane, cyclohexane,decahydronaphthalene, n-decane, isododecane, and tridecane; aromatichydrocarbon solvents, such as benzene, toluene, xylene, tetralin,veratrole, diethylbenzene, methylnaphthalene, nitrobenzene,o-nitrotoluene, mesitylene, indene, and diphenyl sulfide; ketones, suchas acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophenone,propiophenone, diisobutyl ketone, and isophorone; halogenatedhydrocarbon solvents, such as dichloromethane, chloroform, andchlorobenzene; ether solvents, such as diethyl ether, tetrahydrofuran,diisopropyl ether, methyl t-butyl ether, dioxane, dimethoxyethane,diglyme, phenetole, 1,1-dimethoxy cyclohexane, and diisoamyl ether;ester solvents, such as ethyl acetate, isopropyl acetate, diethylmalonate, 3-methoxy-3-methylbutyl acetate, γ-butyrolactone, ethylenecarbonate, propylene carbonate, dimethyl carbonate, andα-acetyl-γ-butyrolactone; nitrile solvents, such as acetonitrile, andbenzonitrile; sulfoxide-based solvents, such as dimethyl sulfoxide, andsulfolane; and amide solvents, such as N,N-dimethyl formamide,N,N-dimethyl acetamide, N-methylpyrrolidone,1,3-dimethyl-2-imidazolidinone, N,N-dimethyl acrylic amide, N,N-dimethylacetoacetoamide, N,N-diethyl formamide, and N,N-diethyl acetamide.

Preferable examples of solvents include ether solvents, such as diethylether, tetrahydrofuran, diisopropyl ether, methyl t-butyl ether,dioxane, dimethoxyethane, diglyme, phenetole, 1,1-dimethoxy cyclohexane,and diisoamyl ether; and amide solvents, such as N,N-dimethyl formamide,N,N-dimethyl acetamide, N-methylpyrrolidone,1,3-dimethyl-2-imidazolidinone, N,N-dimethyl acrylic amide, N,N-dimethylacetoacetoamide, N,N-diethyl formamide, and N,N-diethyl acetamide.

The solvent is preferably inert to the starting material compound, thecatalyst, and the product in step A.

The solvents can be used singly, or in a combination of two or more.

When the compound represented by formula (1) has a low boiling point,the solvent for use is preferably an organic solvent having a highboiling point (e.g., 100° C. or more, more preferably 120° C. or more)from the standpoint of ease of compound purification. The use of such anorganic solvent enables purification of the compound represented byformula (1) simply by distillation.

When the compound represented by formula (1) has a high boiling point,the use of a solvent having a low boiling point suitably enablespurification of the compound represented by formula (1).

The amount of the solvent for use is not particularly limited as long aspart or all of the starting materials are dissolved at the reactiontemperature. For example, the solvent is used in an amount of 0.2 to 50parts by weight, or 0.5 to 30 parts by weight per part by weight of thecompound represented by formula (2).

Step A is preferably performed in the absence of water. The compound orreagent (e.g., a base such as an amine), and the solvent (which includesthe alcohol represented by formula (3), which can serve as a solvent)all possibly containing water and used in step A are preferably driedbefore use. The drying treatment can be performed, for example, by usinga distillation technique, a dehydrating agent such as a molecular sieve,a commercially available dehydrated solvent, or a combination thereof.

The use of a compound or reagent and/or a solvent that is not dried mayreduce the yield and selectivity of the desired product, α-fluoroacrylicacid esters, because of the generation of α-fluoroacrylic acids asby-products.

Step A can be performed in the presence of a polymerization inhibitor.The polymerization inhibitor may be added before the reaction in step Aor at a given point in time during the reaction in step A.

Examples of polymerization inhibitors include amine compounds, such asaliphatic primary amines, aliphatic secondary amines, aliphatic tertiaryamines, alicyclic secondary amines, alicyclic tertiary amines, aromaticamines, heterocyclic amines, and polymer-supported amine compounds(polymeric amine compounds); ammonia; terpene compounds; and compoundscontaining at least one atom selected from the group consisting ofoxygen and sulfur.

Examples of aliphatic primary amines include methylamine, ethylamine,propylamine, butylamine, pentylamine, hexylamine, cyclohexylamine, andethylenediamine.

Examples of aliphatic secondary amines include dimethylamine,diethylamine, dipropylamine, dibutylamine, dipentylamine, dihexylamine,and dicyclohexylamine.

Examples of aliphatic tertiary amines include trimethylamine,triethylamine, diisopropylethylamine, tri(n-butyl)amine, andN,N,N′,N′-tetramethylethylenediamine.

Examples of alicyclic secondary amines include piperidine, piperazine,pyrrolidine, and morpholine.

Examples of alicyclic tertiary amines include N-methylpiperazine,N-methylpyrrolidine, 1,5-diazabicyclo[4,3,0]-5-nonene, and1,4-diazabicyclo[2,2,2]octane.

Examples of aromatic amines include aniline, methyl aniline,dimethylaniline, N,N-dimethylaniline, haloaniline, and nitroaniline.

Examples of heterocyclic amines include pyridine, melamine, pyrimidine,piperazine, quinoline, and imidazole.

Examples of polymer-supported amine compounds (polymeric aminecompounds) include polyethyleneimine, polyallylamine, andpolyvinylpyridine.

Examples of terpene compounds include α-pinene, camphene, α-terpinene,D-limonene, γ-terpinene, p-cymene, and terpinolene.

Preferable examples of compounds containing at least one atom selectedfrom the group consisting of oxygen and sulfur include

C₆₋₂₀ compounds containing at least one 6-membered aromatic carbocyclicring and at least one oxygen atom or sulfur atom directly attached to atleast one carbon atom constituting the ring structure(s) of the at leastone 6-membered aromatic carbocyclic ring. Specific examples includehydroquinone, 4-methoxyphenol, 2,5-di-tert-butylhydroquinone,methylhydroquinone, tert-butylhydroquinone (TBH), p-benzoquinone,methyl-p-benzoquinone, tert-butyl-p-benzoquinone,2,5-diphenyl-p-benzoquinone, 2,6-di-tert-butyl-4-methylphenol (BHT), andphenothiazine.

The amount of the polymerization inhibitor to be added is typicallywithin the range of 0.0001 to 0.1 g, preferably 0.001 to 0.05 g, andmore preferably 0.005 to 0.02 g per gram of the compound represented byformula (1). The polymerization inhibitor, when used in an amount withinthese ranges, can suitably function.

The time period for the reaction can be determined, for example, on thebasis of the desired starting material conversion and yield. Thespecific time period is typically 1 to 24 hours, and preferably 6 to 18hours.

The time period for the reaction can be shortened by applying a higherreaction temperature.

In the production process according to the present invention, theconversion of the starting material may be preferably 70% or more, morepreferably 80% or more, and still more preferably 90% or more.

In the production process according to the present invention, theselectivity of the compound represented by formula (1) may be preferably90% or more, and more preferably 95% or more.

In the production process according to the present invention, the yieldof the compound represented by formula (1) may be preferably 85% ormore, and more preferably 90% or more.

The compound represented by formula (1) obtained by the productionprocess according to the present invention can optionally be purified bya known purification technique, such as solvent extraction, desiccation,filtration, distillation, condensation, and a mixture thereof.

In particular, since the production process according to the presentinvention generates only an extremely small amount of by-products anddecomposed products, the process can provide a high-purity compoundrepresented by formula (1) by using a simple technique such asdistillation.

EXAMPLES

The following examples describe the present invention in more detail.However, the present invention is not limited to these examples.

Comparative Example 1

9.45 g (75.64 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 50.5 mg (0.072 mmol) ofdichlorobis(triphenylphosphine)palladium(II), and 36 mL of methanoldried beforehand were placed in a 150-mL stainless autoclave, and 1.0MPaG carbon monoxide was introduced thereto, followed by stirring at100° C. for 14 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added thereto as an internal standardsubstance, followed by stirring. The mixture was then allowed to standfor a short period of time to precipitate the salt. The supernatant wasdiluted with deuterated chloroform, and subjected to quantificationbased on ¹⁹F-NMR integral values. The diluted supernatant was found tocontain 53.02 mmol (yield: 70.1%) of 2-fluoroacrylic acid methyl esterand 20.88 mmol (recovery: 27.6%) of unreacted 1-bromo-1-fluoroethene.The conversion was 72.5%, and the selectivity was 96.7%.

Example 1

8.76 g (70.11 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 51.5 mg (0.072 mmol) ofdichloro[bis(diphenylphosphinophenyl)ether]palladium(II), and 36 mL ofmethanol dried beforehand were placed in a 150-mL stainless autoclave,and 1.0 MPaG carbon monoxide was introduced thereto, followed bystirring at 100° C. for 13 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 60.08 mmol(yield: 85.7%) of 2-fluoroacrylic acid methyl ester and 9.11 mmol(recovery: 13.0%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 86.8%, and the selectivity was 98.7%.

Example 2

8.88 g (71.07 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 54.4 mg (0.072 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),and 36 mL of methanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 8 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 64.03 mmol(yield: 90.1%) of 2-fluoroacrylic acid methyl ester and 5.83 mmol(recovery: 8.2%) of unreacted 1-bromo-1-fluoroethene. The conversion was91.0%, and the selectivity was 99.0%.

Example 3

9.11 g (72.93 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 54.4 mg (0.072 mmol) ofdichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II), and 36mL of methanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 12 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 65.27 mmol(yield: 89.5%) of 2-fluoroacrylic acid methyl ester and 7.07 mmol(recovery: 9.7%) of unreacted 1-bromo-1-fluoroethene. The conversion was90.1%, and the selectivity was 99.3%.

Example 4

8.80 g (70.43 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 12.8 mg (0.072 mmol) of palladium chloride(II), 4.5 mg(0.072 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and 36 mLof methanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 14 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 54.65 mmol(yield: 77.6%) of 2-fluoroacrylic acid methyl ester and 14.23 mmol(recovery: 20.2%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 78.9%, and the selectivity was 98.3%.

Example 5

9.14 g (73.16 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 12.8 mg (0.072 mmol) of palladium chloride(II), 32.4 mg(0.072 mmol) of 1,4-bis(dicyclohexylphosphino)butane, and 36 mL ofmethanol dried beforehand were placed in a 150-mL stainless autoclave,and 1.0 MPaG carbon monoxide was introduced thereto, followed bystirring at 100° C. for 14 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 58.09 mmol(yield: 79.4%) of 2-fluoroacrylic acid methyl ester and 13.46 mmol(recovery: 18.4%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 81.0%, and the selectivity was 98.0%.

Example 6

8.95 g (71.63 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 2.7 mg (0.0036 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),and 36 mL of methanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 8 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 59.81 mmol(yield: 83.5%) of 2-fluoroacrylic acid methyl ester and 10.60 mmol(recovery: 14.8%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 84.9%, and the selectivity was 98.3%.

Example 7

9.02 g (72.19 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 54.4 mg (0.072 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),and 36 mL of ethanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 8 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 63.46 mmol(yield: 87.9%) of 2-fluoroacrylic acid ethyl ester and 7.29 mmol(recovery: 10.1%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 88.6%, and the selectivity was 99.2%.

Example 8

8.86 g (70.91 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 54.4 mg (0.072 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),4.61 g (0.144 moL) of methanol, and 36 mL of tetrahydrofuran driedbeforehand were placed in a 150-mL stainless autoclave, and 1.0 MPaGcarbon monoxide was introduced thereto, followed by stirring at 100° C.for 7 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 60.42 mmol(yield 85.2%) of 2-fluoroacrylic acid methyl ester and 9.43 mmol(recovery: 13.3%) of unreacted 1-bromo-1-fluoroethene. The conversionwas 86.0%, and the selectivity was 99.1%.

Example 9

8.94 g (71.55 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 54.4 mg (0.072 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),4.61 g (0.144 moL) of methanol, and 36 mL of N-methylpyrrolidone driedbeforehand were placed in a 150-mL stainless autoclave, and 1.0 MPaGcarbon monoxide was introduced thereto, followed by stirring at 100° C.for 7 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 62.75 mmol(yield: 87.7%) of 2-fluoroacrylic acid methyl ester and 7.01 mmol(recovery: 9.8%) of unreacted 1-bromo-1-fluoroethene. The conversion was89.1%, and the selectivity was 98.4%.

Example 10

7.12 g (35.4 mmol) of 2-bromo-2-fluorovinylbenzene, 4.01 g (39.6 mmol)of triethylamine, 27.2 mg (0.036 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),and 18 mL of methanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 9 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 32.64 mmol(yield: 92.2%) of 2-fluoro-3-phenyl acrylic acid methyl ester and 1.88mmol (recovery: 5.3%) of unreacted 2-bromo-2-fluorovinylbenzene. Theconversion was 93.6%, and the selectivity was 98.5%.

Example 11

8.11 g (35.1 mmol) of 1-(2-bromo-2-fluorovinyl)-4-methoxybenzene, 4.01 g(39.6 mmol) of triethylamine, 27.2 mg (0.036 mmol) ofdichloro[4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene]palladium(II),and 18 mL of ethanol dried beforehand were placed in a 150-mL stainlessautoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followedby stirring at 100° C. for 9 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 30.54 mmol(yield: 87.0%) of 2-fluoro-3-(4-methoxyphenyl)acrylic acid ethyl esterand 3.47 mmol (recovery: 9.9%) of unreacted1-(2-bromo-2-fluorovinyl)-4-methoxybenzene. The conversion was 89.3%,and the selectivity was 97.4%.

Example 12

8.98 g (71.87 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 51.5 mg (0.072 mmol) ofdichloro[bis(diphenylphosphinophenyl)ether]palladium(II), and 36 mL ofnon-dried methanol were placed in a 150-mL stainless autoclave, and 1.0MPaG carbon monoxide was introduced thereto, followed by stirring at100° C. for 13 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 50.93 mmol(yield: 70.9%) of 2-fluoroacrylic acid methyl ester, 10.13 mmol (yield:14.1%) of 2-fluoroacrylic acid, and 8.12 mmol (recovery: 11.3%) ofunreacted 1-bromo-1-fluoroethene. The conversion was 87.5%, and theselectivity was 81.0%.

Example 13

8.89 g (71.15 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) oftriethylamine, 51.5 mg (0.072 mmol) ofdichloro[bis(diphenylphosphinophenyl)ether]palladium(II), 75.0 mg (0.34mmol) of 2,6-di-tert-butyl-4-methylphenol, and 36 mL of methanol driedbeforehand were placed in a 150-mL stainless autoclave, and 1.0 MPaGcarbon monoxide was introduced thereto, followed by stirring at 100° C.for 13 hours.

After completion of the reaction, the autoclave was cooled, and theunreacted gas was purged. The autoclave was opened, and 186 mg (1.0mmol) of hexafluorobenzene was added as an internal standard substance,followed by stirring. The mixture was then allowed to stand for a shortperiod of time to precipitate the salt. The supernatant was diluted withdeuterated chloroform, and subjected to quantification based on ¹⁹F-NMRintegral values. The diluted supernatant was found to contain 62.85 mmol(yield: 88.3%) of 2-fluoroacrylic acid methyl ester and 6.81 mmol(recovery: 9.6%) of unreacted 1-bromo-1-fluoroethene. The conversion was90.4%, and the selectivity was 97.7%.

INDUSTRIAL APPLICABILITY

The present invention enables the production of α-fluoroacrylic acidesters useful as intermediates for synthesis at a high starting materialconversion and a high yield.

1. A process for producing a compound represented by formula (1):

wherein R¹ and R² are the same or different and each represent alkyl,fluoroalkyl, aryl optionally substituted with at least one substituent,halogen, or hydrogen; and R³ represents alkyl, fluoroalkyl, or aryloptionally substituted with at least one substituent, the processcomprising step A of reacting a compound represented by formula (2):

wherein the symbols are as defined above, with carbon monoxide and analcohol represented by formula (3):R³—OH   (3) wherein the symbol is as defined above, in the presence of atransition metal complex catalyst containing at least one bidentatephosphine ligand and a base to thereby obtain the compound representedby formula (1).
 2. The process according to claim 1, wherein R¹represents hydrogen or aryl, and R² represents hydrogen or aryl.
 3. Theprocess according to claim 1, wherein the transition metal is palladium.4. The process according to claim 1, wherein the at least one bidentatephosphine ligand contains two aromatic rings that are linked through anoxygen-containing linking group.
 5. The process according to claim 1,wherein the transition metal complex catalyst is used in an amount of0.001 moles or less per mole of the compound represented by formula (2).6. The process according to claim 1, wherein the base is an amine. 7.The process according to claim 1, wherein step A is performed at atemperature within the range of 60 to 120° C.